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Novel compositions and methods of preventing or ameliorating abnormal thrombus formation and cardiovascular disease

a technology of thrombosis and composition, applied in the direction of biocide, antibody medical ingredients, peptide/protein ingredients, etc., can solve the problems of osmotically accumulated osmotically, depletion of reducing equivalents, etc., and achieve the effect of increasing cardiovascular risk

Active Publication Date: 2014-05-29
YALE UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The invention is about a method for treating or preventing conditions such as platelet hyperactivity or abnormal thrombus formation in a person with diabetes or increased cardiovascular risk. The method involves administering a pharmaceutical composition containing an aldose reductase inhibitor, such as tolrestat, epalrestat, or ranirestat, and aspirin or a salt thereof. The invention also includes a pharmaceutical composition containing both an aldose reductase inhibitor and aspirin or a salt thereof. The method can be carried out using various administration routes such as inhalational, oral, rectal, vaginal, parenteral, topical, transdermal, pulmonary, or nasal. The invention also includes a kit containing an aldose reductase inhibitor and aspirin or a salt thereof for use in treating or preventing the condition.

Problems solved by technology

However, under hyperglycemia, the activity of AR is substantially increased, representing up to 30% of total glucose consumption, and the abnormal activation of the polyol pathway leads to depletion of reducing equivalents and accumulation of osmotically active polyols (Bhatnagar & Srivastava, 1992, Biochem. Med. Metab. Biol.

Method used

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  • Novel compositions and methods of preventing or ameliorating abnormal thrombus formation and cardiovascular disease
  • Novel compositions and methods of preventing or ameliorating abnormal thrombus formation and cardiovascular disease
  • Novel compositions and methods of preventing or ameliorating abnormal thrombus formation and cardiovascular disease

Examples

Experimental program
Comparison scheme
Effect test

example 1

Thromboxane Biosynthesis In Vivo in Diabetics vs. Non Diabetics

[0173]Hyperactive platelets and abnormal thrombus formation may be a critical component in the development of diabetic micro- and macro-vascular disease. In the following studies, the relationship between glucose, TXB2 generation and platelet activation in human platelets was systematically investigated, and thromboxane levels in diabetic patients with and without thrombosis were analyzed. In addition to highlighting the importance of glucose regulation of platelet activity through TXA2 generation and release, the study identified platelet aldose reductase as a key transducer of plasma glucose in regulating platelet activity.

[0174]As illustrated in FIG. 1, there was increased TXA2 generation in vivo (as measured by a major urinary TX metabolite, TX-M) in patients with diabetes mellitus. TX-M was examined in diabetic patients (n=102) and compared to a small group of normal volunteers (healthy subjects, HS; n=10), with all...

example 2

Human Platelet Aggregation and Activation are Exquisitely Sensitive to Glucose Concentrations

[0175]The effects of glucose on activation were studied in platelets isolated from venous blood of healthy subjects. The aggregation induced by 1 μg / mL collagen was increased when platelets were pre-incubated with increasing concentrations of glucose (FIGS. 2A & 2C). Interestingly, there was no effect of glucose on ADP-induced aggregation (FIGS. 2B & 2C), as measured by percent of light transmission. To further validate this observation, flow cytometry was performed using P-selectin antibodies and a similar dose dependent effect of glucose on platelet activation was observed in response to collagen but not ADP (FIGS. 2D, 2E &2F). This highlights a sensitivity of human platelets to incremental doses of glucose (5.5-25 mmol / L) when stimulated by collagen. Important questions remained as to the mechanism and how this relates to the initial clinical observations of increased TX-M in diabetic pat...

example 3

AR Contributes to Collagen-Induced Platelet Aggregation Under Normal and High Glucose Conditions

[0176]The effect of 5.5 or 25 mmol / L glucose (basal or hyperglycemia) was tested on human platelets in the presence or absence of epalrestat (selective aldose reductase inhibitor). As shown in FIG. 3, glucose again potentiated the collagen-stimulated aggregation in human platelets. In response to 1 μg / mL collagen, the aggregation in 25 mmol / L glucose was 25% higher than that in 5.5 mmol / L glucose, and was attenuated by treatment with 1-10 mmol / L epalrestat (FIG. 3A-C), suggesting that such aggregation was abolished by inhibition of AR. The concentration of epalrestat used in the present study was based on the dose response curve (FIG. 14). To corroborate the spectrophotometric aggregation assays, P-selectin, the marker for platelet activation, was analyzed using flow cytometry. As in FIG. 2F, collagen-induced P-selectin surface expression was enhanced in HG compared to NG (FIG. 3D-3F), an...

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Abstract

The invention includes compositions and methods useful for treating preventing abnormal thrombus formation and subsequent cardiovascular disease in diabetic patients and patients with increased cardiovascular risk.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]The present application is entitled to priority under 35 U.S.C. §119(e) to U.S. Provisional Patent Application No. 61 / 494,657, filed Jun. 8, 2011, all of which is hereby incorporated by reference in its entirety herein.BACKGROUND OF THE INVENTION[0002]Accelerated atherosclerosis and microvascular disease contribute to the morbidity and mortality associated with diabetes mellitus (Beckman et al., 2002, JAMA 287:2570-2581; D'Souza et al., 2009, Mol. Cell. Biochem. 331:89-116; Kannel & McGee, 1979, JAMA 241:2035-2038). Vascular inflammation, endothelial dysfunction associated with hyperglycemia, impaired fibrinolysis and increased coagulation factors, as well as abnormal platelet function, are typical for diabetes, contributing to the increased thrombotic events and development of arteriosclerosis (Carr, 2001, J. Diabetes Complications 15:44-54). Altered platelet function in diabetes mellitus (DM), including altered adhesion and aggregation,...

Claims

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Application Information

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IPC IPC(8): A61K39/395A61K31/616A61K31/426A61K31/499A61K31/713A61K31/428A61K31/502A61K31/4747A61K31/517A61K31/197A61K31/4162
CPCA61K39/3955A61K31/197A61K31/4162A61K31/426A61K31/428A61K31/713A61K31/499A61K31/502A61K31/517A61K31/616A61K31/4747A61K31/195A61K31/353A61K31/425C12Y101/01021C12N15/1137C12N2310/14
Inventor HWA, JOHNTANG, WAIHO
Owner YALE UNIV
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